Despite its position as a major cause of human disability, the pathogenesis of osteoarthritis still remains to be defined in sufficient detail to permit a rational approach to arresting its progress or to its prevention. Since it is primarily a disease affecting a major segment of the population in later life, some aspect of the aging process must set the stage for its development. This proposal marshalls the expertise of individuals from a wide range of disciplines, ranging from magnetic resonance imaging and molecular genetics, to clinical medicine and orthopedics to focus their skills on age-related changes in structural biology, chemical composition, metabolic activity, humoral response and genetic expression of both rabbit and human joint structures and the effect of various stages of osteoarthritis on these measurements. Correlations will also be made with the signals obtained with nuclear magnetic resonance in both imaging and spectroscopic modes with the objective of enhancing our ability to use this non- invasive procedure for early diagnosis. The departments of the University represented include: Chemistry, Surgery, Radiology, Medicine and Pediatrics and from Scripps Clinic and Research Foundation, the Division of Clinical Immunology. The frequent association of chondrocalcinosis with osteoarthritis increases progressively with advancing age, thus giving reason for further delineation of the underlying metabolic basis for the high pyrophosphate content of cartilage cells, fibroblasts and lymphoblasts cultured from patients affected with chondrocalcinosis, an observation first made at UCSD. Reports of an increased activity of 2 enzymes of purine nucleotide degradation in some of these patients, the involvement of purine synthesis in cell replication and efficacy of a purine-containing therapeutic agent recently reported, provides good reason for detailed tests for alterations in purine metabolism in these cell types. To distinguish between intrinsic and extrinsic factors mediating development of osteoarthritis, they will investigate the differences in responsiveness of different types of chondrocytes in culture to hormones, neuropeptides, cytokines, growth factors. anti-oxidants and various chemical agents as well as the induction and regulation of the proteolytic enzyme collagenase and its inhibitors. The basic information generated holdS promise of providing rational approaches to the development and monitoring of new therapeutic agents with the clinical objective of improving the early diagnosis and treatment of osteoarthritis.